Fri Nov 18 2022

82 articles - From Friday Nov 11 2022 to Friday Nov 18 2022

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Guidelines

Guidelines and related publications, position statements, white papers, technical reviews, consensus statements, etc…

Ann Oncol

Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.

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Meta-analysis

meta-analyses and systematic reviews

Lancet Haematol

Second primary malignancies in patients with haematological cancers treated with lenalidomide: a systematic review and meta-analysis.

Further investigations are needed to improve understanding on why lenalidomide only promotes SPM in patients with multiple myeloma. Funding None.

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Original articles

RCT, clinical trials, retrospective studies, etc…

Blood

-----NRX-0492 Degrades Wildtype and C481 Mutant BTK and Demonstrates in vivo Activity in CLL Patient Derived Xenografts.

Oral bioavailability, >90% degradation of BTK at sub-nanomolar concentrations and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022).

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A Novel RIPK1 Inhibitor Reduces GVHD in Mice via a Non-immunosuppressive Mechanism that Restores Intestinal Homeostasis.

Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective non-immunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.

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Aging drives Tet2+/- clonal hematopoiesis via IL-1 signaling.

In agreement, IL-1a-treated Tet2+/- HSCs showed increased DNA replication and repair transcriptomic signatures and reduced susceptibility to IL-1a-mediated downregulation of self-renewal genes. Importantly, genetic deletion of IL-1R1 in Tet2+/- HPSC or pharmacological inhibition of IL-1 signaling impaired Tet2+/- clonal expansion, establishing the IL-1 pathway as a relevant and therapeutically targetable driver of Tet2+/- CHIP progression during aging.

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Biallelic deletion of 1p32 defines ultra-high-risk myeloma, but monoallelic del(1p32) remains a strong prognostic factor.

In the multivariate analysis, del(1p32) appeared as a negative prognostic factor; after adjustment for age and treatment, the risk of progression was 1.3 times higher among patients harboring del(1p32), and the risk of death was 1.9 times higher. At the dawn of risk-adapted treatment strategies, we have confirmed the adverse impact of del(1p32) in MM and the relevance of its assessment at diagnosis.

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BTG1 inactivation drives lymphomagenesis and promotes lymphoma dissemination through activation of BCAR1.

Furthermore, following BTG1 deletion or expression of BTG1 mutations observed in DLBCL patients, the overactivation of the BCAR1-RAC1 pathway confers increased migration ability in vitro and in vivo. These modifications are targetable with the SRC inhibitor dasatinib, which opens novel therapeutic opportunities in BTG1 mutated DLBCL.

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Essential thrombocythemia: challenges in clinical practice and future prospects.

In this review we provide a practical overview of diagnosis and management of ET with a focus upon difficult patient scenarios and some consideration of what comprehensive care might require. Finally, we also discuss newer therapies and how these might be assessed.

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FLT3ITD drives context-specific changes in cell identity and variable interferon dependence during AML initiation.

Thus, common AML driver mutations, such as FLT3ITD, can co-opt different mechanisms of transformation in different genetic contexts. Furthermore, pediatric-biased NUP98 fusions convey actionable interferon dependence.

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How we diagnose and treat acute graft-versus-host disease after solid organ transplantation.

For GVHD involving the marrow we initiate an allogeneic hematopoietic cell donor search early. In this article, we describe three cases of GVHD after SOT, outline our approach to diagnosis and management, and then provide analysis of the three instructive cases.

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Hydroxyurea is associated with lower malaria incidence in children with sickle cell anemia in sub-Saharan Africa.

Hydroxyurea at MTD is associated with lower malaria incidence in SCA through incompletely defined mechanisms, but treatment-associated mild myelosuppression with ANC < 3.0 x 109/L is salutary. Splenomegaly represents an unexplained risk factor for malaria infections among children with SCA in Africa.

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Integrating Novel Agents into the Treatment of Advanced Mycosis Fungoides and Sézary Syndrome.

To gain the full benefit of these novel agents, we must develop strategies to match treatments to the patients most likely to benefit from them. Here, we consider both the current approaches to treatment selection based on clinical features and the future of molecular biomarker-guided therapy for patients with this heterogeneous disease.

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Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis.

Altered distribution of filamin A and actin and delocalization of the von Willebrand Factor were also demonstrated. Overall, this study expands our knowledge of GALE-related thrombocytopenia and emphasized the critical role of GALE in the physiological glycosylation of key proteins involved in platelet production and function.

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Secreted Mutant Calreticulins As Rogue Cytokines in Myeloproliferative Neoplasms.

Thus, secreted mutant CALR proteins will act more specifically on the MPN clone. In conclusion, a chaperone, CALR, can turn into a rogue cytokine through somatic mutation of its encoding gene.

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Blood Adv

A phase 1/2 study of lenalidomide and obinutuzumab with CHOP for newly diagnosed DLBCL.

LO-CHOP demonstrates high efficacy and tolerability in newly diagnosed DLBCL, leading to a high rate of undetectable minimal residual disease by ctDNA by end of therapy. This trial is registered at as NCT02529852.

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Applying CRISPR-Cas9 screens to dissect hematological malignancies.

Specifically, within blood cancers, current CRISPR screens have specifically focused on improving our understanding of drug resistance strategies, disease biology, development of novel therapeutic approaches, and identifying the molecular mechanisms of current therapies, with an underlying aim of improving disease outcomes. Here, we review the development of CRISPR-Cas9 genome editing strategy, explicitly focusing on the recent advances in the CRISPR-Cas9 based screening approaches, its current capabilities, limitations, and future applications in the context of hematological malignancies.

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Carfilzomib Combined with Rituximab, Ifosfamide, Carboplatin, and Etoposide for Relapsed or Refractory DLBCL.

C-R-ICE is well tolerated in pts with R/R DLBCL with toxicities comparable to R-ICE therapy. Our data show that pts with non-GCB DLBCL benefit significantly from incorporating CFZ into second-line therapy and HDC-ASCT.

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CNL and aCML should be considered as single entity based on molecular profiles and outcomes.

We identified four high-risk mutated genes, specifically CEBPA (ß=2.26, HR=9.54, p=0.003), EZH2 (ß=1.12, HR=3.062, p=0.009), NRAS (ß=1.29, HR=3.63, p=0.048) and U2AF1 (ß=1.75, HR=5.74, p=0.013) by multivariate analysis. Our findings underscore the relevance of molecular-risk classification in CNL/aCML as well as the importance of CSF3R mutations in these diseases.

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Efficacy, Safety, and Molecular Response Predictors of Oral Ixazomib and Short-Course Rituximab in Untreated iNHL.

Ixazomib demonstrated efficacy alone and with short course rituximab in untreated iNHL while exhibiting favorable toxicity, convenience, and retention of B-cell immune response. This trial is registered at as NCT02339922.

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Histone Deacetylase-6 Modulates the Effects of 4oC Platelets on Vascular Endothelial Permeability.

In addition, angiopoietin-2 (Ang-2), an inducer of vascular leak and antagonist of Ang-1, inhibited PLT barrier protection, suggesting involvement of the Tie-2 pathway. This study demonstrates that HDAC-6 inhibition with tubacin attenuates the diminished vasculo-protective properties of 4oC PLTs, and these properties may be independent of PLT circulation time.

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Low toxicity and excellent outcomes in patients with DLBCL without residual lymphoma at the time of CD19 CAR T-cell therapy.

Our findings suggest that, in patients with R/R DLBCL who have an indication for CAR T-cell therapy, treating patients in complete remission at time of infusion is feasible, safe, and associated with favorable disease control. Further exploration in a larger clinical trial setting is warranted.

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Pharmacokinetics, pharmacodynamics, safety and efficacy of crizanlizumab in patients with sickle cell disease.

Results here demonstrate the PK/PD properties of crizanlizumab in SCD patients, and the potential sustained efficacy and long-term safety of the drug after >12 months' treatment. This trial is registered at as NCT03264989.

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Safety and Immunogenicity of V114, a 15-valent Pneumococcal Conjugate Vaccine, in Children with Sickle Cell Disease (PNEU-SICKLE).

Trial Registration: ClinicalTrials. gov: NCT03731182; EudraCT: 2018-001152-35.

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Targeting platelet GPVI with glenzocimab: a novel mechanism for inhibition.

Glenzocimab did not bind to a truncated GPVI missing loop residues 129-136, thus validating the epitope identified in the crystal structure. Overall, these findings demonstrate that the binding of glenzocimab to the D2 domain of GPVI induces steric hindrance and structural modifications that drive the inhibition of GPVI interactions with its major ligands.

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The complement receptor C3AR constitutes a novel therapeutic target in NPM1-mutated AML.

Mechanistically, stimulation of C3AR-expressing cells with C3a, the ligand of C3AR, leads to activation of ERK1/2 and increased survival of AML cells, suggesting that this is an important signaling axis in this subtype of AML. Finally, we show that antibodies directed against C3AR efficiently elicit NK cell-mediated killing of primary AML cells ex vivo, highlighting C3AR as a candidate therapeutic target in NPM1-mutated AML.

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Underweight children over 5 years with sickle cell anemia are at risk for early mortality in a low-resource setting.

Underweight participants (weight-for-age z-score < -1) had a greater probability of death during follow-up than those not underweight (p=0.043). Underweight status in school-aged children with sickle cell anemia is a previously unrecognized risk factor for early mortality in Nigeria and can be easily applied to screen children at risk for death.

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Blood Cancer J

Evaluating complete remission with partial hematologic recovery (CRh) as a response criterion in myelodysplastic syndromes (MDS).

MDS patients who achieve a CRh response had similar survival and duration on therapy as patients who achieve CR response and superior to other IWG responses. These data support further evaluation of CRh into future response criteria and clinical trials.

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Haematologica

Allogeneic, Off-the-Shelf, SARS-CoV-2-specific T cells (ALVR109) for the treatment of COVID-19 in high risk patients.

In conclusion, this study establishes the feasibility of preparing and delivering off-the-shelf SARS-CoV-2-directed VSTs to patients with COVID-19 and supports the clinical use of VSTs outside of the profoundly immune compromised setting (ClinicalTrials. gov number, NCT04401410).

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Animal models of Diamond-Blackfan anemia: updates and challenges.

In the past decades, researchers have made significant progress in understanding the pathogenesis of DBA, but it remains unclear how the ubiquitous RP haploinsufficiency causes the erythroid-specific defect in hematopoiesis in DBA patients, and why there is a difference in penetrance and spontaneous remission among individuals who carry identical mutations. In this paper, we provide a comprehensive review of the development of DBA animal models and discuss the future research directions for these important experimental systems.

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Axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma patients in complete metabolic response.

Not available.

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Clinical response to dabrafenib and chemotherapy in clonally-related histiocytosis and acute lymphoblastic leukemia.

Not available.

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Clonal hematopoiesis in diffuse large B-cell lymphoma: clinical impact and genetic relatedness to lymphoma and therapy-related myeloid neoplasm.

Not available.

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Contribution of fetal microchimeric cells to maternal wound healing in sickle cell ulcers.

In a retrospective cohort of SCD patients, we demonstrated using several parameters that ever parous SCD women had a decreased burden related to leg ulcers compared to nulliparous women. Taken together, these results indicate that healing capacities of FMC are maintained long after delivery and may be targeted to promote wound healing in post-partum SCD patients.

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Diffuse large B-cell lymphoma in octogenarians aged 85 and older can benefit from treatment with curative intent: a report on 129 patients prospectively registered in the Elderly Project of the Fondazione Italiana Linfomi (FIL).

Clinical characteristics were similar between LO and EO, but LO more frequently received palliation (50% vs 23%: P=0.001) and had worse 2-year overall survival (OS) (48% vs 63%: P=0.001) and 2-year progression-free survival (PFS) (43% vs 56%: P=0.01). Patients receiving anthracycline did better than patients receiving palliation (P.

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Disrupting autophagy in FLT3-mutant AML.

Not available.

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Dysfunctional subsets of CD39+ T cells, distinct from PD-1+, driven by leukemic extracellular vesicles in myeloid leukemias.

Not available.

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How different are blood platelets from women or men, young or elderly people?

Not available.

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Longitudinal analysis of the evolution of cellular immunity to SARS-CoV-2 induced by infection and vaccination.

Not available.

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Monoclonal gammopathy of increasing significance: time to screen?

We review the literature and case for MG screening in this paper. In particular, we highlight areas that require focus to establish screening for MG.

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Prevention and management of secondary central nervous system lymphoma.

In this review we focus on the identification of high-risk patients, prophylaxis strategies and recent treatment approaches for SCNSL. The incorporation of novel agents to immunochemotherapy deserves further study in prospective trials.

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J Hematol Oncol

Phase 1 study of intraventricular 131I-omburtamab targeting B7H3 (CD276)-expressing CNS malignancies.

cRIT with 131 I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases.

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Lancet Haematol

Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial.

The results of this phase 1 study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies. Funding Forma Therapeutics.

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Leukemia

Genetic deletion and pharmacologic inhibition of E3 ubiquitin ligase HOIP impairs the propagation of myeloid leukemia.

Finally, the administration of thiolutin, which inhibits the catalytic activity of Hoip, improved the survival of recipients in murine myeloid leukemia and suppressed propagation in the patient-derived xenograft model of myeloid leukemia. Collectively, these data indicate that inhibition of LUBAC activity may be a valid therapeutic target for myeloid leukemia.

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Gilteritinib activity in refractory or relapsed FLT3-mutated acute myeloid leukemia patients previously treated by intensive chemotherapy and midostaurin: a study from the French AML Intergroup ALFA/FILO.

Multivariate analyses for prognostic factors associated with OS identified female gender (HR 1.61), adverse cytogenetic risk (HR 2.52), and allogenic HSCT after gilteritinib (HR 0.13). Although these patients were more heavily pretreated, these real-world data reproduce the results of ADMIRAL and provide new insights into the course of patients previously treated by intensive chemotherapy and midostaurin and beyond the 2nd line of treatment who can benefit from treatment in an outpatient setting.

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Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma.

Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL.

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mTOR inhibition amplifies the anti-lymphoma effect of PI3Kß/d blockage in diffuse large B-cell lymphoma.

Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kß/d signaling and thus identifies a previously unappreciated role of the PI3Kß isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kß/d and mTOR is effective in al major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.

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Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy.

The selective BCL-2 inhibitor, venetoclax, exhibited in vitro additivity in combination with hypomethylating or conventional chemotherapeutic agents. The addition of venetoclax to azacitidine resulted in a significant in vivo survival advantage indicating the therapeutic potential of this combination to improve outcome for infants with KMT2A-rearranged ALL.

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VIP152 is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy in chronic lymphocytic leukemia.

Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.

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Thromb Haemost

Assessment of DOAC in GEriatrics (ADAGE study): rivaroxaban/apixaban concentrations and thrombin generation profiles in NVAF very elderly patients.

Our study provides original data in very elderly patients receiving DOAC in real-life setting, showing great inter-individual variability in plasma concentrations and TG parameters. Further research is needed to understand the potential clinical impact of these findings.

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Genetic predisposition of both waist circumference and hip circumference increased the risk of venous thromboembolism.

There is a significant causal relationship between WC/HC and VTE/PE, which is consistent with observational studies. Taking measures to reduce WC/HC of obesity may help reduce the incidence of VTE/PE.

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Obesity and the Risk of Venous Thromboembolism after Major Lower Limb Orthopaedic Surgery: A Literature Review.

Hence any increase in dosage may require intensive surveillance for the residual anticoagulant effects and careful balancing of risks and benefits on an individual basis. Our review discusses the basis for increased thrombotic risk in obesity, the evidence supporting dosage recommendations, and the implications of the current guidelines for pharmacological thromboprophylaxis in patients with obesity undergoing lower limb arthroplasty.

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Reviews&Editorials

Plenty of the editorials are available as full text through the publisher website using the provided link

Am J Hematol

Venetoclax and hypomethylating agent therapy in myelodysplastic syndromes: big picture perspective.

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Blood

A challenging choice: consolidation in Ph+ ALL.

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AML gets upSET when its dietary needs are unMet.

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Cardiotoxicity in patients treated with acalabrutinib.

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Giving alloHSCT a needed LIF(t).

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Mechanisms of resistance to venetoclax.

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Protecting the fetus from FNAIT.

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RBC, heal thyself: PK activators in SCD.

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Transferrin-induced thrombosis in hypoxia.

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Miscellaneous

misc publications eg case reports, tools of the trade, images of the month, etc…

Blood

Allogeneic HCT for Ph+ ALL in CR1 with CMR.

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Blast phagocytosis.

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Platelet satellitism in immune thrombocytopenic purpura.

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Risks of therapy-related hematologic neoplasms beyond myelodysplastic syndromes and acute myeloid leukemia.

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Blood Adv

Abramson JS, Siddiqi T, Garcia J, et al. Cytokine release syndrome and neurological event costs in lisocabtagene maraleucel-treated patients in the TRANSCEND NHL 001 trial. Blood Adv. 2021;5(6):1695-1705.

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Chari A, Cho HJ, Dhadwal A, et al. A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma. Blood Adv. 2017;1(19):1575-1583.

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Curing CLL: one clone at a time.

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Megakaryocyte buds are distinct from microvesicles and likely to represent platelet precursors.

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Severe Autoimmune intravascular hemolytic anemia in patients receiving Alemtuzumab for Multiple sclerosis.

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Smith CC, Levis MJ, Perl AE, et al. Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib. Blood Adv. 2022;6(7):2144-2155.

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CA Cancer J Clin

Multidisciplinary considerations in the maintenance treatment of poly(ADP-ribose) polymerase inhibitors for homologous recombination-proficient, advanced-stage epithelial ovarian cancer.

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Haematologica

Identification of multiple genetic loci associated with RBC alloimmunization in mice.

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Leukemia

Frequency and prognostic implications of KMT2A rearrangements in children with precursor B-cell lymphoma.

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Letters&Replies

Letters to the editors and authors’ replies

Am J Hematol

SARS-CoV-2 mRNA vaccination of aplastic anemia patients is safe and effective.

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Blood Cancer J

Breakthrough infections in MPN-COVID vaccinated patients.

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Characteristics of measurable residual disease assessment in myeloma: a review of clinical trials from 2015-2020.

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In response to: Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: results of the iStopMM study.

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Increased risk of thrombosis in JAK2 V617F-positive patients with primary myelofibrosis and interaction of the mutation with the IPSS score.

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J Hematol Oncol

Preclinical evaluation of combination nemtabrutinib and venetoclax in chronic lymphocytic leukemia.

In an adoptive transfer CLL mouse model, mice treated with nemtabrutinib and venetoclax had prolonged survival compared to mice treated with ibrutinib and venetoclax. Our preclinical studies further validate the combination of BTK inhibitors with venetoclax and justify further investigation of combining nemtabrutinib with venetoclax in CLL.

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SIRPa-Fc fusion protein IMM01 exhibits dual anti-tumor activities by targeting CD47/SIRPa signal pathway via blocking the "don't eat me" signal and activating the "eat me" signal.

Finally, IMM01 demonstrated a favorable safety profile with no human RBC binding activity or hemagglutination induction. IMM01 inhibits the growth of tumor cells by the following three possible mechanisms: (1) directly activating macrophages to phagocytize tumor cells; (2) activated macrophages degrade phagocytized tumor cells and present tumor antigens to T cells through MHC molecules to activate T cells; (3) activated macrophages can convert "cold tumors" into "hot tumors" and increase the infiltration of immune cells through chemotaxis by secreting some cytokines and chemokines.

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Leukemia

Not only mutations but also tumorigenesis can be substantially attributed to DNA damage from reactive oxygen species in RUNX1::RUNX1T1-fusion-positive acute myeloid leukemia.

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Should we give oligomonocytic chronic myelomonocytic leukemia a higher prominence in the next WHO Classification of Haematolymphoid Tumors?

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